Evolving notions on immune response in colorectal cancer and their implications for biomarker development

Grizzi, Fabio; Basso, Gianluca; Borroni, Elena Monica; Cavalleri, Tommaso; Bianchi, Paolo; Štifter, Sanja; Chiriva‐Internati, Maurizio; Malesci, Alberto; Laghi, Luigi

doi:10.1007/s00011-017-1128-1

Cited by 34 publications

(25 citation statements)

References 188 publications

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“…[15][16][17] More importantly, several recent studies even pointed out that immunological data (the type, density, and location of immune cells within the tumor samples) are a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. 17,18 However, we noted that the prognostic value of certain TIICs subpopulation does not always consistent with each other even in studies with same experiment design. For instance, one study provided evidence for a role of FoxP3 + Treg density in CRC tissue as predictor of prolonged survival.…”

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confidence: 75%

“…Additionally, mature T cells and dendritic cells, memory T cells were commonly detected TIICs subpopulation with favorable prognostic, while immune suppressive regulatory T cells are associated with impaired prognosis in CRC . More importantly, several recent studies even pointed out that immunological data (the type, density, and location of immune cells within the tumor samples) are a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer …”

Section: Introductionmentioning

confidence: 99%

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Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression‐based study

et al. 2018

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Immune infiltration of colorectal cancer (CRC) is closely associated with clinical outcome. However, previous work has not accounted for the diversity of functionally distinct cell types that make up the immune response. In this study, based on a deconvolution algorithm (known as CIBERSORT) and clinical annotated expression profiles, we comprehensively analyzed the tumor‐infiltrating immune cells present in CRC for the first time. The fraction of 22 immune cells subpopulations was evaluated to determine the associations between each cell type and survival and response to chemotherapy. As a result, profiles of immune infiltration vary significantly between paired cancer and paracancerous tissue and the variation could characterize the individual differences. Of the cell subpopulations investigated, tumors lacking M1 macrophages or with an increased number of M2 macrophages, eosinophils, and neutrophils were associated with the poor prognosis. Unsupervised clustering analysis using immune cell proportions revealed five subgroups of tumors, largely defined by the balance between macrophages M1, M2, and NK resting cells, with distinct survival patterns, and associated with well‐established molecular subtype. Collectively, our data suggest that subtle differences in the cellular composition of the immune infiltrate in CRC appear to exist, and these differences are likely to be important determinants of both prognosis and response to treatment.

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confidence: 75%

Section: Introductionmentioning

confidence: 99%

Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression‐based study

et al. 2018

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“…13 Immune reaction plays a key role in suppressing tumor development and progression, [14][15][16] and high-level infiltrates of lymphocytes in colorectal cancer have been associated with better clinical outcomes. [17][18][19][20][21][22] Four tumor subtypes can be created based on the TIME framework, [9][10][11][12] including the CD274 high /TIL present subtype (TIME 2) which generally responds to immunotherapy, the CD274 low /TIL present subtype (TIME 3) which suggests presence of other suppressor pathways in immune tolerance, the CD274 high /TIL absent subtype (TIME 4) which indicates intrinsic induction of the CD274 pathway, and the CD274 low /TIL absent subtype (TIME 1) which reflects immune "ignorance. "…”

Section: Introductionmentioning

confidence: 99%

TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

et al. 2018

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Inhibitors targeting the (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor ( ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, /TIL; TIME 2, /TIL; TIME 3, /TIL; and TIME 4, /TIL). In survival analyses, Cox proportional hazards models were adjusted for potential confounders, including microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, LINE-1 methylation level, and ,, and mutation status. TIME subtypes 1, 2, 3 and 4 had 218 (27%), 117 (14%), 103 (13%), and 374 (46%) colorectal cancer cases, respectively. Compared with TIL-absent subtypes (TIME 1 and 4), TIL-present subtypes (TIME 2 and 3) were associated with high-level MSI, high-degree CIMP, mutation, and higher amounts of neoantigens ( < 0.001). TIME subtypes were not significantly associated with colorectal cancer-specific or overall survival. In conclusion, TIL-present TIME subtypes of colorectal cancer are associated with high levels of MSI and neoantigen load, supporting better responsiveness to cancer immunotherapy. Further studies examining tumor molecular alterations and additional factors in the tumor microenvironment may inform development of immunoprevention and immunotherapy strategies.

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“…The overall tumor microenvironment (TME) is composed of a wide variety of stromal and immune cell types, as well as extracellular components such as the extracellular matrix (ECM) and a range of cytokines and growth factors [11]. The speci c composition of the TME can in uence rates of tumor progression, and the modulation of the immune cell subsets that compose the TIME represents an attractive therapeutic strategy for the treatment of a range of tumor types [12,13].…”

Section: Introductionmentioning

confidence: 99%

Identified and Validated the Characterization of the Colorectal Cancer Tumor Immune Microenvironment

Han¹,

Chen

Yang³

2020

Preprint

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Background While the administration of immunotherapy can facilitate the development of durable anti-tumor immunity in certain colorectal cancer (CRC) patients.This study was therefore designed to conduct a robust analysis of the CRC immune microenvironment to identify specific genes and pathways that can be targeted in an effort to achieve more effective immunotherapy outcomes. Methods Using five Independent data sets, we analyzed expression profiles associated with 29 different immune signatures, and we used these profiles to guide the hierarchical clustering of CRC samples based on their immune microenvironmental composition. Results We were able to cluster our CRC samples based on whether they had exhibited high, medium, or low levels of infiltration by immune cell types associated with tumor clearance (Immunity_H, Immunity_M, and Immunity_L, respectively). Samples in the Immunity_H subset exhibited a “hot” immune microenvironment, with higher stromal scores, higher immune scores, and lower tumor purity. The microsatellite instability (MSI) group included the majority of the Immunity_H samples, whereas most Immunity_M and Immunity_L samples were incorporated into the microsatellite stability (MSS) .The vast majority of patients with KRAS mutations were in the Immunity_L and MSS groups, whereas the majority of patients exhibiting BRAF V600E mutations were found in the Immunity_H and MSI-H samples. TMB high samples included a majority of the Immunity_H samples and a small subset of the Immunity_M samples. Conclusions Our results identify three reproducibly validated immune subtypes of CRC tumor samples, potentially offering valuable insights that may guide the immunotherapeutic treatment of these patients.

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Evolving notions on immune response in colorectal cancer and their implications for biomarker development

Abstract: The introduction of immune signatures and cellular and molecular components of the immune system as biomarkers is particularly important considering the increasing use of immune-based cancer therapies as therapeutic strategies for cancer patients.

Cited by 34 publications

References 188 publications

Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression‐based study

Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression‐based study

TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

Identified and Validated the Characterization of the Colorectal Cancer Tumor Immune Microenvironment

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